Possible Contribution of Inflammation-Associated Hypoxia to Increased K(2P)5.1 K(+) Channel Expression in CD4(+) T Cells of the Mouse Model for Inflammatory Bowel Disease

Previous studies have reported the up-regulation of the two-pore domain K(+) channel K(2P)5.1 in the CD4(+) T cells of patients with multiple sclerosis (MS) and rheumatoid arthritis (RA), as well as in a mouse model of inflammatory bowel disease (IBD). However, the mechanisms underlying this up-regulation remain unclear. Inflammation-associated hypoxia is involved in the pathogenesis of autoimmune diseases, such as IBD, MS, and RA, and T cells are exposed to a hypoxic environment during their recruitment from inflamed tissues to secondary lymphoid tissues. We herein investigated whether inflammation-associated hypoxia is attributable to the increased expression and activity of K(2P)5.1 in the splenic CD4(+) T cells of chemically-induced IBD model mice. Significant increases in hypoxia-inducible factor (HIF)-1α transcripts and proteins were found in the splenic CD4(+) T cells of the IBD model. In the activated splenic CD4(+) T cells, hypoxia (1.5% O(2)) increased K(2P)5.1 expression and activity, whereas a treatment with the HIF inhibitor FM19G11 but not the selective HIF-2 inhibitor exerted the opposite effect. Hypoxia-exposed K(2P)5.1 up-regulation was also detected in stimulated thymocytes and the mouse T-cell line. The class III histone deacetylase sirtuin-1 (SIRT1) is a downstream molecule of HIF-1α signaling. We examined the effects of the SIRT1 inhibitor NCO-01 on K(2P)5.1 transcription in activated CD4(+) T cells, and we found no significant effects on the K(2P)5.1 transcription. No acute compensatory responses of K(2P)3.1–K(2P)5.1 up-regulation were found in the CD4(+) T cells of the IBD model and the hypoxia-exposed T cells. Collectively, these results suggest a mechanism for K(2P)5.1 up-regulation via HIF-1 in the CD4(+) T cells of the IBD model.